Spontaneous loss-of-function dock2 mutation alters murine colitis sensitivity and is a confounding variable in inflammatory bowel disease research

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Abstract

Background: Dextran sodium sulfate (DSS)-induced colitis is the most commonly used mouse model of inflammatory bowel disease (IBD) due to its acute nature, reproducibility, and phenotypic overlap with human disease. Following an unexpected and sharp decline in DSS-induced colitis susceptibility in our commercially acquired C57Bl/6 wild-type mice, we discovered that a spontaneous loss-of-function mutation in dedicator of cytokinesis 2 (Dock2Hsd) was responsible. Presence of this mutation in research colonies has the capacity to broadly impact preclinical IBD studies. Methods: DSS-colitis was induced in weight-, age-, and gender-matched C57Bl/6NHsd mice. Daily treatment with vehicle or the glutamate carboxypeptidase II (GCPII) inhibitor, 2-PMPA (100 mg/kg IP), was performed and disease activity index was monitored. At termination, colon GCPII activity was measured. Results: DSS-treated Dock2Hsd mice developed more severe colitis, had significantly increased colon GCPII activity and were more sensitive to pharmacologic inhibition of GCPII. Conclusions: The Dock2Hsd mutation is a confounding variable of high relevance to the IBD research community. Dock2Hsd mice were distributed as wild-type C57Bl/6 for multiple years and thus it is unknown how prevalent this mutation is in investigator-maintained colonies of C57Bl/6-derived mice. In our research, presence of the Dock2Hsd mutation caused enhanced GCPII colon activity more closely resembling human disease, providing a useful platform for screening GCPII inhibitors for preclinical efficacy. However, unanticipated presence of Dock2Hsd in genetically modified mice used to study IBD pathobiology can confound conclusions. Thus, care must be taken when interpreting studies performed in mice of C57Bl/6 lineage where Dock2 status is unknown.

Original languageEnglish (US)
JournalCrohn's and Colitis 360
Volume1
Issue number3
DOIs
StatePublished - Oct 1 2019

Keywords

  • Animal models
  • C57Bl/6
  • DSS-colitis
  • Inflammatory bowel disease
  • Preclinical studies

ASJC Scopus subject areas

  • Gastroenterology

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